1. Field of the Invention
The present invention relates to medicament compositions for nasal administration of vaccines, pharmacologically active peptides such as peptide hormones, physiologically active proteins, or enzyme proteins.
2. Description of the Related Art
In recent years, new vaccines and pharmacologically active peptides have been produced with increasing frequency in accordance with the progress of molecular biology and peptide synthesis techniques. Vaccine research efforts have worked to support the extensive diphtheria, pertussis, polio, measles, and tuberculosis vaccination programs carried out in developing countries. In particular, research on infant vaccines has worked: (1) to reduce side-effects, to enhance quality control, and to improve mucosal immunity through non-injected vaccine administration methods; (2) to develop slow-releasing adjuvants for use in single-administration vaccines; (3) to produce heat-resistant live vaccines so as to preserve their activity (40.degree. C., 3 weeks); and (4) to develop mixed vaccines.
Vaccine research efforts in developed countries have focused on the production of novel influenza vaccines, especially in response to the needs of geriatric medicine. While vaccines are regularly administered to a wide variety of patients, essentially only one method of administration has been employed: subcutaneous injection. This is because effective immunological resistance has not been reliably produced by means of oral, percutaneous, rectal, or hypoglossal administration due to the physical properties of those tissue types.
Nasal administration of component vaccines has been anticipated as a desirable and convenient method, where satisfactory immunological resistance has not been obtained by means of conventional antigen administration methods.
Pharmacologically active peptides, such as insulin, calcitonin, elcatonin, salmon calcitonin, buserelin acetate (Gn-RH derivatives), leuprorelin acetate (LH-RH derivatives), somatropin, and glucagon, are medicines indispensable for the treatment of many fatal or serious diseases. However, all of these are poorly absorbed through the normal gastro-intestinal, rectal, or hypoglossal mucosa, or the skin. Furthermore, they are deactivated by proteases in the digestive system. Therefore, pharmacological effects by means of oral, percutaneous, gastro-intestinal, or hypoglossal administration thereof are hardly expected. Accordingly, insulin, buserelin acetate, and leuprorelin acetate are administered subcutaneously, while elcatonin and calcitonin are injected intramuscularly.
Administration by means of injection, particularly, subcutaneous injection, considerably harms the quality of life of patients, because of the frequent infliction of pain with repeated injections which are required in many cases due to quick metabolism of the agent in the body. Therefore, convenient methods of administration, such as oral, ophthalmic, and nasal administration are preferable when effective, since repeated injection is not only harmful to the skin of the patient, but also increases the risk of injection with contaminated needles and compounds the problem of contaminated medical waste disposal.
Recently, it has been recognized that it would be highly beneficial to develop non-injection administration methods for patients to repeatedly self-administer vaccine- or pharmacologically active peptide-based medicines and thereby prolong the pharmacological effects thereof. However, it has generally been found difficult to produce pharmacologically effective, bioavailable levels of peptide-based medicines by means other than injection, such as oral, percutaneous, gastro-intestinal, rectal, or subcutaneous administration. Based on this observation, nasal administration has been tried as a means of achieving pharmacologically effective levels of peptide-based medicines. As a result, several commercial, solution- or suspension-based nasal spray products have become available. Most of these, however, produce only local irrigation, sterilization, analgesic, or anti-inflammatory effects.
Nasal administration methods which induce systemic effects have been studied with respect to various medicines, but with little practical outcome so far because they do not provide sufficient absorption to produce systemic pharmacological effects, they cause irritation to the nasal mucosa, they produce unpleasant odors, and the active component of the medicines is unstable in the nasal cavity.
However, with regard to calcitonin, effective nasal sprays and freon-gas-propelled suspension sprays have been developed, and buserelin nasal drops have also been marketed. This approach has been successful for those two peptides because they are directly absorbed by the capillaries supplying the nasal mucosa and are thus transferred into the general circulation, thereby producing their pharmacological effects. Nevertheless, these active peptide products are likewise not satisfactory in that they irritate the mucosa and do not allow efficient absorption to be sustained. With reference to the nasal drops, leakage from the nasal cavity after administration remains a significant shortcoming.